Naphthacene derivatives

ABSTRACT

Naphthacene derivatives of the formula:   WHEREIN R1 represents an oxygen atom or a group of the formula   IN WHICH R4 represents hydrogen or an alkyl, alkanoyl, thioalkanoyl, aryl, aroyl, carbamoyl, thiocarbamoyl or amidino group, these groups being optionally substituted, and R5 represents hydrogen, or R4 and R5 together with the nitrogen atom to which they are attached represent piperazin-1-yl which carries on the second nitrogen atom an optionally substituted alkyl group, R2 represents hydrogen, or an alkyl group, an aminoalkyl radical which is optionally substituted on the amino group, or an aryl, aralkyl, heterocyclyl or heterocyclylalkyl group and R3 represents hydrogen, or R2 and R3 together represent an alkylene group containing three to six carbon atoms, and salts thereof, possess antitumor properties.

United States Patent Primary Examiner-Norma S. MilestoneAttorney-Stevens, Davis, Miller Mosher Inventors Appl. No.

Filed Patented Assignee Priority NAPHTHACENE DERIVATIVES Jean BouchludonABSTRACT: Naphthacene derivatives of the formula:

Moraang-Sur-Orge; C Georges Jolles, Sceaux, both of France 0 0H 779,632II I I-Rr Nov. 27, 1968 OH Dec. 14, 1971 Rhone-Poulenc S. A. 0

Paris, France i H 1 OH O CHCH2-CHCHCH-CHa Nov. 28, 1967 (EH 0 0 FranR2-CHC0NH 0H 130018 a t I v I v R NH wherein R, represents an oxygenatom or a group of the formula /Ra N-N in which R represents hydrogen oran alkyl, alkanoyl,

7 Claims, No Drawings thioalkanoyl, aryl, aroyl, carbamoyl,thiocarbamoyl or [1.5. CI. amidino group these groups being opuonanysubstitutgd and 424/283 R represents hydrogen, or R and R together withthe In C07. 7/04 nitrogen atom to which they are attached representpiperazinand Wm, y which carries on the second nitrogen atom anoptionally Field M Search 260/345 7 substituted alkyl group, Rrepresents hydrogen, or an alkyl group, an aminoalkyl radical which isoptionally substituted on the amino group, or an aryl, aralkyl,heterocyclyl or heterocyclylalkyl group and R represents hydrogen, or Rand R together represent an alkylene group containing three to sixcarbon atoms, and salts thereof, possess antitumor properties.

NAPHTHACENE DERIVATIVES CH OH I C=Ri in which R, represents a hydrogenatom or an alkyl, alkanoyl, thioalkanoyl, aryl (e.g. phenyl), aroyl(e.g. benzoyl), carbamoyl, thiocarbamoyl or amidino group, these groupsbeing optionally substituted, and R, represents a hydrogen atom, or Rand R, together with the nitrogen atom to which they are attachedrepresent a piperazin-l-yl group which carries on the second nitrogenatom an optionally substituted alkyl group, R, represents a hydrogenatom or an alkyl group, an aminoalkyl radical which is optionallysubstituted on the amino group, or an aryl, aralltyl, heterocyclyl orheterocyclylalkyl group and R, represents a hydrogen atom, or R, and R,together represent a straightor branched-chain alkylene group containingthree to six carbon atoms, and salts thereof. The substituents which maybe present on the groups R, and on the alkyl group in the 4-position ofthe piperazinyl ring when represents a 4alkyl-piperazin-l-yl group arepreferably substituents of acid or basic character which are able toimprove the solubility of the naphthacene derivatives of formula I inwater. Preferably the substituents are quaternary ammonium and sulfonicacid groups, or residues of amino acids and of peptides. The alltyl,alkanoyl and thioalkanoyl groups or moieties mentioned above preferablycontain at most four carbon atoms.

According to a feature of the present invention, the naphthacenederivatives of general formula I are prepared by the process whichcomprises reacting an amino acid of the general formula:

(wherein R, and a, are as hereinbefore defined) with a naphthacenederivative of the general formula:

(wherein R, is as hereinbefore defined) or an acid addition .salt;thereof, by methods known per se in peptide chemistry for converting aprimary amino group into a grouping By the term methods known per se" asused in this specification is meant methods heretofore used or describedin the chemical literature.

In the aforesaid process it is particularly advantageous to protect theamino group and to activate the carboxy group of the amino acid ofgeneral formula ll. It is possible, for example, simultaneously toprotect the amino group and activate the carboxy group by preparing anN-carboxyanhydride of the general formula:

R z-C H- O O \O IV wherein R, and R, are as hereinbefore defined, byreaction of phosgene with the amino acid of general formula II.

Reaction of the naphthacene derivative of formula III with theN-carboxyanhydride of formula IV is generally effected in an aqueous oraqueous-organic medium buffered to a pH of between 8 and l l and at atemperature of about 0 C.

It is also possible to protect the amino group(s) of the amino acid ofgeneral formula II and then to activate the acid group.

The protective group on the amino group(s) may optionally be removedsubsequent to the reaction, by methods known per se which do not effectthe rest of the molecule. Preferred protecting groups are trityl andt.-butoxycarbonyl, which may be removedby hydrolysis in a. diluteacidmedium. Where the amino acid of formula II has several amino groups, aselective elimination of the protective group on the amino group in thea-pos'ition-to the carbonyl group canbe" achieved under certainconditions, this group being more labile than groups protecting theother amino groups. a

The acid group of the amino acid of formula [I may be activated byesterification with hydroxy-containing compounds such asN-hydroxysuccinimide, p-nitrophenol, 2,4,5- trichlorophenol or4-hydroxypiperidine. Such activated esters may optionally be prepared insitu.

When the aforesaid process is carried out with an activated andprotected amino acid and a naphthacene compound of formula III, it ispreferably effected in an organic solvent, for example ethyl acetate ordimethylformamide, in the presence of a carbodiimide such asdicyclohexylcarbodiimide at a temperature between 1 5 and +25 C.,optionally in the presence of an organic base such as triethylamine.

When an amino acid of general formula ll, of which the amino group isoptionally protected as mentioned above, is reacted with a naphthacenederivative of formula ill, the reaction can be eflected in an organicsolvent, for example ethyl acetate, dimethylformamide, acetonitrile ormethylene chloride, at a temperature between 0 and 30 C. in the presenceof a carbodiimide such as dicyclohexylcarbodiimide.

The naphthacene starting material of formula III wherein R. representsan oxygen atom is the antibiotic designated number 13,057 R.P., whichhas been given the name daunorubicin. its preparation andphysicochemical properties have been described in the specification ofBritish Pat. No. 985,598 granted to Rhone-Poulenc S.A. on an applicationfiled May 16th, i963. It has since been established that the antibiotichas the formula in, R representing oxygen.

The naphthacene starting materials of general formula III wherein Rrepresents a radical in which R, and R, are as hereinbefore defined, areobtained by the reaction of a compound of the general formula:

tion, the naphthacene derivatives of general formula I wherein Rrepresents a radical (wherein R, and R, are as hereinbefore defined) areprepared by the process which comprises reacting a compound of generalformula V with a naphthacene derivative of general fonnula I wherein R,represents an oxygen atom. The reaction is carried out under the usualconditions for the conversion of ketones to hydrazono compounds, and ispreferably efiected in an inert organic solvent, such as an alcohol(e.g. ethanol) or dimethylformamide, with gentle heating of the reactionmixture.

The .naphthacene derivatives'prepared by the aforementioned processesmay, where appropriate, be converted into acid addition salts or saltswith nitrogen-containing bases, into metal salts or into quaternaryammonium salts. The salts may be obtained by the reaction of thenaphthacene derivatives of formula I with acids or bases in appropriatesolvents. As organic solvents there may be used, for example, alcohols,ethers, ketones, or chlorinated hydrocarbons. The salt which is formedis precipitated, if necessary after concentration of its solution, andis separated by filtration or decantation. The quaternary ammonium saltsmay be obtained by the reaction of esters on the naphthacene bases,optionally in an organic solvent, at room temperature or more rapidlywith gentle heatmg.

The naphthacene derivatives of general formula I and their salts haveinteresting antitumor properties, combined with a low toxicity. Theyhave proved particularly active against leukemia L 1210 (administeredintraperitoneally) in mice. The experiments were carried out on 1 monthold mice weighing l8 to 20 g. intraperitoneally grafted with l leukemiaL 1210 cells and treated daily with doses of the naphthacene derivativesbetween 0.5 and mg./kg.' (i.p.). Preferred compounds of formula I arethose in which R, represents an oxygen atom or a thiocarbamoyl group,and R, represents an alkyl group containing up to four carbon atoms, anaminoalkyl group containing up to four carbon atoms in the alkyl moietyunsubstituted on the amino group or carrying thereon a trityl grouping,or a phenylalkyl group containing up to four carbon atoms in the alkylmoiety, and acid addition salts thereof. Of outstanding importance are4-methoxy-5,l2-dioxo-6,9,l ltrihydroxy-7-(2,3,6-o-tridesoxy-3-N-L-leucylaminol-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12-hexahydronaphthacene and thecorresponding N-D-leucylamino, N-L-phenylalanylamino,N-e-trityl-L-lysylamino and N-L-phenylglycylamino compounds, and4-methoxy-5, l 2-dioxo-6,9,l l-trihydroxy-7-2,3,6-O-Tridesoxy-3-N-L-leucylaminol -L-lyxohexosyl)-9[l-(thiosemicarbazono)ethyl]-5,"l,8,9, l 0, l 2-hexahydronaphthacene, andtheir acid addition salts.

For therapeutic purposes, the naphthacene derivatives of formula i maybe employed as such or in the form of nontoxic salts, i.e. saltscontaining anions which are relatively innocuous to the animal organismin therapeutic doses of the salts, e.g. acid addition salts such ashydrochlorides, sulfates, nitrates, phosphates, acetates, propionates,succinates, benzoates, fumarates, maleates, tartrates,theophyllineacetates, salicylates, phenolphthalinates ormethylcne-bis-B- hydroxynaphthoates, metal salts such as the sodiumsalts, or salts with nitrogen-containing bases. They may also beemployed in the form of nontoxic quaternary ammonium salts obtained byreaction of the napthacene derivatives with organic halides, e.g.methyl, ethyl, allyl or benzyl chloride, bromide or iodide, or otherreactive esters, e.g. methylor ethylsulphates, benzenesulphonates ortoluene-p-sulphonates.

The following examples illustrate the invention. The products of formulaI in which R, represents an oxygen atom obtained by the proceduresdescribed are given asimplified form of nomenclature by replacing4-methoxy-5,l2-dioxo- 6,9,1l-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-substituentamino-1-L-lyxohexosyi)-9-acetyl-5,7,8,9, i 0, l 2-hexahydronephthacene"by N-"substituent"daunorubicin."

EXAMPLE 1 borlc acid potassium chloride N aqueous sodium hydroxidedistilled water 6.184 g. 7.456 g. 88 cc.

to make up to I liter.

The pH of the daunorubicin solution thus obtained is adjusted to 10.2 byaddition of N aqueous sodium hydroxide, and the solution is then cooledto 0 C. The solution is stirred veryvigorously under a nitrogenatmosphere and L-leucine N-carboxyanhydride (0.00l mole) dissolved inacetone (5 cc.) cooled to l0 C. is added. The mixture is stirredvigorously for 5 minutes at 0 C. and under a nitrogen atmosphere. The pHis thereafter adjusted to about 3.5 by means of normal sulphuric acidand the mixture stirred for 15 minutes and then treated with alkali togive pH 7, using normal aqueous sodium hydroxide.

Lyophilization of the solution thus obtained yields a red powder whichis dissolved in a mixture of methanol and l,2- dichloroethane (1:1 byvolume; 20 cc.). The solution is filtered through silica gel g.)contained in a column 20 mm.

in diameter. The filtrate is evaporated to dryness under reducedpressure (20 mm. Hg) at 50 C., taken up in water and then lyophilized.

The resulting powder is dissolved in a mixture of methanol andl,2-dichloroethane (6:4 by volume; 3 cc.), and the solution ischromatographed through a column 17 mm. in diameter containing silicagel (40 g. the fraction eluted with a mixture of methanol andl,2-dichloroethane (7:3 by volume) contains chromatographically pureN-L-leucyldaunorubicin.

The N-L-leucyldaunorubicin obtained by concentrating to dryness underreduced pressure is dissolved in water contain ing 1 equivalent ofhydrochloric acid. The solution thus obtained is lyophilized to yieldN-L-leucyldaunorubicin hydrochloride (0.3 g.).

N% 4.15 (theory 4.13). Rf 0.74 [silica gel; methanol-l,2-dichloroethane(1:1 by volume)].

EXAMPLE 2 Daunorubicin hydrochloride (L39 g.) is dissolved indimethylfon'namide (40 cc.). Triethylamine (0.344 cc.) and theN-trityl-D-leucinate of N-hydroxysuccinimide (1.25 g.) [prepared bycondensing N-trityl-D-leucine with N-hydroxysuccinimide in the presenceof dicyclohexylcarbodiimide in a mixture of ethyl acetate and dioxane]are added. The mixture is stirred for 24 hours at 20 C. and concentratedto dryness under reduced pressure (0.3 mm. Hg) at 50 C. The resultingresidue is taken up in a mixture of 1,2-dichloroethane and methanol (:5by volume). The solution is filtered through silica gel g.) contained ina column 2 cm. in diameter. The filtrate is evaporated to dryness underreduced pressure (20 mm. Hg) at 50 C. to yieldN-trityl-Dleucyldaunorubicin (1.75 g).

Rf 0.90 [silica gel; methanol-1,2-dichloroethane (1:1 by volume)].

This product is taken up in 75 percent acetic acid (100 cc.) and themixture is stirred for 1 hour at 20 C. The reaction medium is cooled toC. and the pH is adjusted to 7 by addition of 15N aqueous ammonia. Theinsoluble material is filtered off and copiously washed with distilledwater. The filtrate is lyophilized and N-D-leucyldaunorubicin (1.12 g.)is obtained in a yield of 71 percent of the theoretical yield.

N% =4.7 (theory 4.37). Rf 0.70 [silica gel; methanol-1,2-dichloroethane(1:1 by volume)].

EXAMPLE 3 By following the procedure of example 1 but starting withdaunorubicin hydrochloride (2.2 g.), a buffer solution (500 cc.),D-leucine-N-carboxyanhydride (0.691 g.) and acetone (25 cc.),N-D-leucyldaunorubicin hydrochloride (200 mg.) is obtained.

Rf 0.70 [silica gel; methanol-l,2-dichloroethane (1:1 by volume)].

EXAMPLE 4 Daumrubicin hydrochloride (100 mg.) is dissolved indimethylformamide (3 cc.). Triethylamine (0.025 cc.) and thetrityl-L-phenylalaninate of N-hydroxysuccinimide (95 mg.) [prepared bycondensing trityl-L-phenylalanine with N- hydroxysuccinimide in thepresence of dicylohexylcarbodiimide in dioxane] are added.

By following the procedure described in example 2, the following aresuccessively obtained: N-trityl-L-phenylalanyldaunorubicin 181 mg.),

Rf 0.90 [silica gel; methannl-1,2-dicl1loroethane (1:1 by volume)], andN-L-phenylalanyldaunorubicin hydrochloride (77 mg.).

N%= 3.8 (theory= 3.93).

Rf 0.83 [silica gel; methanol-l,2-dichloroethane (1:1 by volume)].

EXAMPLE 5 Daunorubicin hydrochloride (100 mg.) and diethylamineditrityl-L-lysinate (129 mg.) are dissolved in dimethylformamide (4cc.), and N-hydroxysuccinimide (27 mg.) is added. After cooling to 0 C.,dicyclohexylcarbodiimide (38 mg.) is added and the mixture is stirredfor 4 hours at 0 C. and then for 20 hours at 20 C. A slight amount ofinsoluble matter is filtered off. The filtrate is concentrated todryness under reduced pressure (0.3 mm. Hg) at 50 C. The resultingresidue is taken up in a mixture of 1,2-dichloroethane and methanol(95:5 by volume). The solution is filtered through silica gel (12 g.)contained in a column 12 mm. in diameter. The filtrate is concentratedto dryness under reduced pressure (20 mm. Hg) at 50 C. to yieldN-ditrityl-L-lysyldaunorubicin (130 mg.).

Rf 0.85 [silica gel; methanol-1,2-dichloroethane (1:1 by volume].

The resulting residue is taken up in 75 percent acetic acid cc.), andthe solution stirred for 1 hour at 20 C. The reaction medium is cooledto 0 C. and the pH is adjusted to 7 by addition of 15N aqueous ammonia.The insoluble matter is filtered otf and copiously washed with distilledwater, and then taken up in a mixture of distilled water (25 cc.) and0.1N hydrochloric acid (2.5 ml.). Insoluble matter is filtered off, andthe filtrate then lyophilized to yield N-(N-e-trityl-L-lysyl)daunorubicin dihydrochloride (60 mg.

N% 3.9 (theory 4.32). Rf 0.77 [silica gel; methanol-1,2-dichloroethane(1:1 by volume)].

EXAMPLE 6 By following the procedure of example 1 but starting withdaunorubicin hydrochloride (2 g.), buffer solution (500 cc.),L-phenylglycine N-carboxyanhydride (0.690 g.) and dioxane (15 cc.),N-L-phenylglycyldaunorubicin hydrochloride (550 mg.) is obtained.

N%=3.85 (theory=4.0l). Rf 0.84 [silica gel; methanol-1,2-dichloroethane(1:1 by volume)].

EXAMPLE 7 N-L-leucyldaunorubicin hydrochloride (0.53 g.) is dissolved inethanol (60 cc.) containing 2.5 percent acetic acid. Thiosemicarbazide(0.072 g.) is added and the mixture then heated for 4 hours at 40 C.with stirring. Thereafter it is stirred for 13 hours at 20 C. andconcentrated to dryness under reduced pressure (20 mm. Hg) at 45 C. Thedry residue is taken up in distilled water cc.), and the resultingsolution lyophilized to yield 4methoxy-5,l2-dioxo-6,9,l1- trihydroxy-7-(2,3,o-o-tridesoxy-S-N-L-Ieucylaminol -L-lyxohexosyl)-9-[l-(thiosemicarbazono)ethyl]-5,7,8,9,10,12-hexahydronaphthacenehydrochloride (0.555 g.).

Rf 0.70 [silica gel; methanol-l,2-dichloroethane (1:1 by volume)].

The present invention includes within its scope pharmaceuticalcompositions which comprise at least one of the naphthacene derivativesof general fonnula l, or a nontoxic salt thereof, in association with apharmaceutically acceptable carrier or coating. In clinical practice thecompounds of the present invention will normally be administered orally,parenterally or rectally.

Solid compositions for oral administration include compressed tablets,pills, powders, and granules. In such solid compositions one or more ofthe active compounds is, or are, admixed with at least one inert diluentsuch as starch, sucrose or lactose. The compositions may also comprise,as is normal practice, additional substances other than inert diluents,e.g. lubricating agents, such as magnesium stearate. Liquid compositionsfor oral administration include pharmaceutically acceptable emulsions,solutions, suspensions, syrups and elixirs containing inert diluentscommonly used in the art, such as water and liquid paraffin. Besidesinert diluents such compositions may also comprise adjuvants, such aswetting and suspending agents, and sweetening, flavoring, perfuming andpreserving agents. The compositions according to the invention, for oraladministration, also include capsules of absorbable materials such asgelatin containing one or more of the active substances with or withoutaddition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions, suspensions, oremulsions. Examples of nonaqueous solvents or suspending media arepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,and injectable organic esters such as ethyl oleate. These compositionsmay also contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporation in thecompositions of sterilizing agents, by irradiation, or by heating. Theymay also be manufactured in the form of sterile solid compositions,which can be dissolved or dispersed in sterile water or some othersterile injectable medium immediately before use.

Compositions for rectal administration are suppositories which contain,in addition to the active substance excipients such as cacao butter, asuitable wax base or solidified glycerin.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. The dosage will dependupon the therapeutic effect sought, the route of administration, thelength of treatment,

and the species of animal. In human therapy, for example in thetreatment of lymophoblastic and myeloblastic forms of acute leukemia,and chronic myeloid leukemia, the composirions should generally beadministered so as to give, in the case of parenteral adminis ration,doses between 2 and 10 mgJkg. of naphthacene derivative per day for anadult.

The following example illustrates pharmaceutical compositions accordingto the invention.

EXAMPLE 8 A solution of the following composition is prepared:

N-L-leucyldaunorubicin hydrochloride distilled water 1. A naphthacenecompound of the formula:

E (]=R1 C 2 1 9 OH wherein R represents an oxygen atom or a group of theformula:

:N-NHCSNH;

R represents hydrogen, alkyl of at most four carbon atoms, aminoalkyl ofat most four carbon atoms unsubstituted or substituted on the aminogroup by trityl, phenyl, or phenylalkyl of at most four carbon atoms inthe alkyl, and nontoxic salts thereof.

2. The naphthacene compound according to claim 1 which is 4-methoxy-5, l2-dioxo-6,9,l l-trihydroxy-7-( 2,3,6-0-tridesoxy-S-N-L-leucylamino-l-L-lyxohexosyl)-9-acetyl-5,7,8,9,l0,l2-hexahydronaphthacene, and nontoxic acid addition saltsthereof.

3. The naphthcene compound according to claim 1 which is 4-methoxy-5, 12dioxo-6,9,l l-trihydroxy-7-( 2,3 ,G-O-Iridesoxy-3-N-Dleucylaminol-blyxohexosyl)-9-acetyl- 5,7,8,9,10,12-hexahydronaphthacene and nontoxicacid addition salts thereof.

4. The naphthacene compound according to claim 1 which is 4-methoxy-5, l2-dioxo-6,9,l l,-trihydroxy-7-( 2,3,6-0-tridesoxy-3-N-L-phenylalanylaminol -L-lyxohexosyl )-9-acetyl-5,7,8,9,10,l2,-hexahydronaphthacene and nontoxic acid additionsalts thereof.

5. The naphthacene compound according to claim 1 which is 4-methoxy-5 l2-dioxo-6,9,l l-trihydroxy-7-( 2,3,6-0-tridesoxy-3-N-e-trityl-L-lysylamino- 1 -L-lyxohexosyl )-9-acetyl-5,7,8,9,10,12-hexahydronaphthacene and nontoxic acid additionsalts thereof.

6. The naphthacene compound according to claim 1 which is 4-methoxy-5 l2-dioxo-6,9,l l-trihydroxy-7-( 2,3 ,6-0-tridesoxy-S-N-L-phenylglycylaminol -L-lyxohexosyl )-9- acetyl-5,7,8,9, l0, l 2-hexahydronaphthacene and nontoxic acid addition salts thereof.

7. The naphthacene compound according to claim 1 which is4-methoxy-5,12-dioxo-6,9,l l-trihydroxy-7-( 2,3 ,6-0-tridesoxy-B-N-L-Ieucylaminol -L-lyxohexosyl )-9-[ l(thiosemicarbazono)ethyl]5,7,8,9,l0,12-hex ahydronaphthacene andnontoxic acid addition salts thereof.

2. The naphthacene compound according to claim 1 which is4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-L-leucylamino-1-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12-hexahydronaphthacene,and nontoxic acid addition salts thereof.
 3. The naphthcene compoundaccording to claim 1 which is4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-D-leucylamino-1-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12-hexahydronaphthaceneand nontoxic acid addition salts thereof.
 4. The naphthacene compoundaccording to claim 1 which is4-methoxy-5,12-dioxo-6,9,11,-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-L-phenylalanylamino-1-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12,-hexahydronaphthacene and nontoxic acid addition salts thereof.
 5. Thenaphthacene compound according to claim 1 which is4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-epsilon-trityl-L-lysylamino-1-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12-hexahydronaphthacene and nontoxic acid addition salts thereof. 6.The naphthacene compound according to claim 1 which is4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-L-phenylglycylamino-1-L-lyxohexosyl)-9-acetyl-5,7,8,9,10,12-hexahydronaphthacene and nontoxic acid addition salts thereof.
 7. Thenaphthacene compound according to claim 1 which is4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(2,3,6-O-tridesoxy-3-N-L-leucylamino-1-L-lyxohexosyl)-9-(1-(thiosemicarbazono)ethyl)-5,7,8,9,10,12-hexahydronaphthacene and nontoxic acid addition salts thereof.